Based on human/mouse comparative sequence analysis we have identified a fourth member of the chromosome 11 apolipoprotein (apoAI, apoCIII, apoAIV) gene cluster which we have named apolipoprotein AV (apoAV). Our recent studies in humans and mice indicate that apoAV is an important determinant of plasma triglyceride levels. In mice, the overexpression of a human apoAV transgene resulted in decreased plasma triglyceride concentrations, while inactivation of the mouse apoAV gene led to increased triglyceride levels. Complementing these mouse findings, three independent human studies consistently showed that two minor apoAV haplotypes are strongly associated with increased triglycerides. These initial investigations indicate that the newly discovered apolipoprotein gene, apoAV, is an important modulator of plasma triglyceride levels in mammals. Accordingly, this grant focuses on deciphering several fundamental properties of apoAV that include: 1) determining the mechanism by which apoAV affects plasma triglycerides and its atherogenic consequences using apoAV transgenic and knockout mice, 2) investigating the factors and DNA sequences involved in the regulation of apoAV expression and 3) using a combination of human haplotype studies and defined manipulations of the mouse genome to identify apoAV single nucleotide polymorphisms (SNPs) that directly participate in determining triglyceride levels in humans.